Acne vulgaris is a common disease which afflicts approximately 90% of all teenagers, and, not uncommonly, affects men and women in their twenties or thirties or may persist in adults for many years. Acne vulgaris most commonly occurs on oily areas of the skin with high sebaceous gland concentration. The areas of high sebaceous gland concentration are the face, ears, retroauricular areas (e. g. behind the ears), chest, back, and occasionally the neck and upper arms.
Acneiform eruptions can occur wherever there is a pilosebaceous unit or sebaceous follicle which does include the entire surface of the skin.
The basic lesion in acne is the comedo commonly known as the blackhead. The comedo is created by retention of layers of dead skin known as keratin in the lining of the follicles. In addition to hyperkeratosis (which is thickening or retentative layering of keratin), there is an accumulation of sebum which is the lipid-laden product of the sebaceous gland. The cells of the sebaceous glands in which sebum originates are the sebocytes. The combination of the keratin and the sebum produces a plugging of the mouth or opening of the follicular canal, and papules are formed by inflammation around the comedones (plural of comedo). Depending upon the degree of inflammation, pustules, cysts, nodules, granulomatous reactions, scars, and keloids may develop.
Most typical forms of mild acne vulgaris demonstrate the predominance of comedones with the occasional pustules. Pustules and papules predominate in more severe cases. These can heal with scars forming; that is, fibrosis of the lesions occurs that are deep and penetrating. In moderately active cases, larger cystic lesions can develop.
Acne vulgaris can appear in many clinical varieties. The mildest case manifests comedones on oily skin and is called acne comedo.
Papular acne is another variety of acne which has many inflammatory papules. This form of acne is common in adolescent skin, but it can be seen in all ages. The papular inflammatory form of acne can progress to an indurated, deeper, and destructive form known as acne indurata. These lesions can produce severe scarring and can be quite deep seated and destructive.
Steroid acne vulgaris can occur when oral corticosteroids or topical steroids are used and occurs as inflammatory follicular papules. When oral corticosteroids are ingested, the inflammatory papules are usually sudden in appearance and can cover the chest, back, arm, and face. When topical corticosteroids are used for more than two weeks, a localized inflammatory papular response can develop which can proceed to a granulomatous chronic reaction known as steroid acne rosacea.
Premenstrual acne can occur in a large number of menstruating women as a papular and pustular acne vulgaris, approximately one week prior to menstruation. There is a body of evidence that implicates a surge in progesterone as the mediator of premenstrual acne.
Preadolescent acne is divided into neonatal, infantile, and childhood forms of acne. The neonatal form is limited to the first few weeks of life. It usually develops a couple of days after birth. It more commonly afflicts males and reveals transient facial papules and pustules which can clear spontaneously in a few days or weeks. The stimulation of neonatal sebaceous glands by circulating maternal progesterone appears to be the cause.
If the acne persists beyond the first month of life, the acne is called infantile acne and can extend into childhood, adolescence, and adult life. The childhood acne can result from a persistent infantile acne or can develop de novo after age two. This form of acne is uncommon, but it has more of a male predilection. It is characterized by comedones commonly in groups, papules, pustules, and, rarely, cysts. This condition can extend from a few weeks to several years and can develop into pubertal acne.
Acne venenata is by definition a comedonal or papular acne which occurs after exposure to chlorinated hydrocarbons (chloracne), cutting oils, petroleum oil, coal tar, and pitches.
Acne cosmetica is a persistent low grade comedonal and/or papular and pustular acne that occurs usually on the chin and cheeks of adult women due to oil-based cosmetics, i. e. foundations, facial creams, and sunscreens.
Pomade acne is a type of acne cosmetica which appears to occur almost exclusively in black persons who apply grease and oil to scalp hair and the face as a grooming aid. The lesions are predominately comedonal acne and can develop into inflammatory acne papules, depending upon the chronicity of the pomade use.
Acne detergicans occurs as a type of comedonal acne in patients who use oil-based cleansing soaps. Acne excoriee, also known as pickers acne, starts out as mild form of papular or comedonal acne which is manipulated or picked and causes further inflammation, more papules, and sometimes scars, pitting, and atrophy of the skin.
Gram negative acne, sometimes called gram negative folliculitis when it extends to the neck, arms, legs, and trunk, is a form of an inflammatory papular, follicular, and pustular response to gram negative organisms including Enterobacter, Klebsiella, Escherichia, Proteus, Serratia, and Pseudomonas. The most characteristic lesion on the face is superficial pustules, or papulo-pustules (which is a combination of a papule and pustule). The face can show diffuse erythema and inflammation surrounding these pustules and juicy papules or papulo-pustules.
The gram negative acne is usually highly resistant and usually occurs in patients who have bad inflammatory papular acne for long periods or who have been treated with long term oral administration of antibiotics such as tetracycline, erythromycin, or minocycline or topical antibiotics such as topical clindamycin or topical erythromycin. Subsequent to the oral administration tetracycline or erythromycin, oral administration of amoxicillin, ampicillin, and trimethoprin-sulfomethoxazole has been shown to be effective in treating this disease. (Poli, F., Prost, C., Revuz, J., Gram-negative Folliculitis, Ann. Dermatol. Venereol., 115:797-800, 1988). In another reference, Marks, R. and Ellis, J., "Comparative effectiveness of tetracycline and ampicillin in rosacea", Lancet 1971 vol 2 pages 1049-1052, there is a disclosure that ampicillin has been used orally for treatment of rosacea. More specifically, orally administered ampicillin was compared with orally administered tetracycline in the treatment of rosacea.
Acne rosacea is an inflammatory eruption that is chronic and occurs on the face, especially on the nose as well as the scalp and neck, in some instances. It is manifested by erythema, pustules, papules, telangieclasia (which is dilation of superficial capillaries), and hypertrophy of sebaceous glands. The middle portions of the face are most frequently involved. The eyes and eyelids are not uncommonly involved and can produce inflammation and infection of the conjunctiva, eyelids, and hypertrophy of the meibomian glands. Acne rosacea is often called simply rosacea and is most common in middle aged women and men. Rosacea can go on to form a granulamatous roscea which is characterized by resistant inflammatory papules which when biopsied reveal noncaseating epithelial cell granulomas.
Pseudofolliculitis barbae is a predominantly male affliction which is characterized by inflammatory papules and pustules on the bearded area of the face most commonly in black persons, but all racial groups can be affected. The mechanism is thought to be an inflammatory response to the end of hair (usually curly beard facial hair) into the skin causing a foreign body inflammatory response.
Folliculitis is an inflammatory reaction around the hair follicle which can be bacterial or nonbacterial in nature. Predominately, folliculitis is caused by gram positive organisms such as Staphylococcus and Streptococcus, and less frequently by gram negative bacteria discussed hereinabove with respect to gram negative folliculitis.
Perioral dermatitis is a common papular inflammatory eruption which is confined around the mouth. It most commonly afflicts women in their early twenties to middle thirties, but it can be seen in adolescents and more mature adults.
Hidradenitis suppurativa is a suppurative (chronic) and cystic disease of apocrine gland regions of the skin, including the axillae and groin.
There is a genetic tendency to acne, in particular acne congoblata which is a deep cystic and sinus forming type of acne. This condition is essentially a deep, aggressive form of cystic acne occurring in the apocrine gland regions. Topical administration of clindamycin has been used to treat this form of cystic acne.
The etiology of acne vulgaris and related disorders as discussed above is not completely known in every detail. However, what is known is that acne, in general, is caused by a plurality of factors. In general, there are four main factors that cause acne: genetics; hormonal activity; bacteria; and the inflammatory response.
Genetics is a prominent component as it is well known that several members of the same family can be affected with moderate to severe scarring acne. The inheritance by some is thought to be autosomal dominant, but this has not been definitively proven. Furthermore, on the molecular level, there has not yet been discovered a gene or group of genes that are responsible for the various forms of acne vulgaris.
Another key factor in the development of acne is hormonal. In adolescence, for example, it is thought that androgens can interact with receptors on the sebaceous glands and cause stimulation of the sebaceous gland to hypertrophy and hence form more sebaceous production of lipids and free fatty acids which distend the follicular canal. More specifically, there is evidence for increased peripheral metabolic conversion of the androgen testosterone to dihydrotestosterone at the level of the skin in acne patients. It is further hypothesized that receptors on the sebaceous gland for the active androgen dihydrotestosterone can exhibit various degrees of sensitivity, and that a heightened sensitivity response may be partially or entirely genetically predetermined.
Another causative factor in acne is the presence of bacteria in the follicular canal. Within the follicular canal are bacteria which are indigenous to the follicular lining. They are anaerobic, gram positive organisms called Propionibacterium acnes. It is interesting to note that they are present in abundance in pathologically affected sites. They are reduced during oral antimicrobial treatment, and their absence from nonhuman animal skin is striking especially since animals do not exhibit acne vulgaris.
Yet another causative factor in acne is the inflammatory response manifested in the skin. More specifically, it is thought that Propionibacterium acnes lives in symbiosis on the keratin lined follicular canal. Propionibacterium acnes ingests the sebum produced from the sebocytes of the sebaceous glands. This nascent sebum is largely lipid in composition and also contains DNA, RNA, proteins, and other cellular components that result from the breakdown of sebocytes themselves. The Propionibacterium acnes which are highly lipophilic, feed on the nascent sebum. It has been shown that Propionibacterium acnes are found only in sebaceous rich areas. If the nutrients increase due to an active and large sebaceous system, then colonization and high growth rates of Propionibacterium acnes will form. It has been shown that the resident bacterial flora will produce biologically active molecules such as histamine, extracellular enzymes, and peptides which may be responsible for the chemotaxis of the inflammatory infiltrate in acne vulgaris. Since the follicular lining in the pilosebaceous unit is intact, it has been theorized that if colonization of Propionibacterium acnes occurs in sufficient numbers, they could produce initiating autogenic molecules that promote the initiating of inflammation. Propionibacterium acnes can produce proteinases, lipase, and hyaluronate lyase all of which may serve as the catalysts or initiators of the inflammatory infiltrate which has been shown to be composed of neutrophils and lymphocytes.
A number of treatments are presently known for treating acne, some more successful than others. Some modes of treatment have been mentioned above. There are two basic ways to administer a therapeutic agent: topical and systemic.
Aside from treatments mentioned above, some additional systemic treatments for acne that are presently employed are: oral tetracycline; oral erythromycin; minocycline; doxycycline; oral trimethoprim-sulfamethoxazole and isotretinoin (ACCUTANE.TM.).
Those that have been suggested in the past and that are no longer generally employed include: antibacterial vaccines; estrogen therapy; dietary restrictions; and vitamin therapy (e. g. oral ingestion of vitamin A).
Some of the topical treatments that are presently employed are: topical erythromycin, clindamycin, benzoyl peroxide, 2% sulfur, 3% resorcinol, a tetracycline derivative (meclocycline sulfosalicylate 1%), 2% salicylic acid, and tretinoin (Retin-A.TM.).
Topical treatments that have been suggested in the past and that are no longer generally employed include: x-ray treatment; electric sparks; vitamin therapy; treatment with a plant extract as described in U.S. Pat. No. 4,803,069.
More specifically with respect to the topical use of certain specific antibiotics, a topical solution, ointment, and gel containing erythromycin is used. Also used is a topical solution, gel, and lotion containing clindamycin, and a cream containing meclocycline sulfosalicylate (a tetracycline derivative).
Some of the undesirable side effects of orally administered antibiotics are abdominal cramps, black tongue, cough, diarrhea, fatigue, irritation of the mouth, loss of appetite, nausea, vomiting, fever, hearing loss, jaundice, rash, rectal and vaginal itching, and superinfection.
It is noted that erythromycin is produced by the bacterium Streptomyces erytheus and that erythromycin has a chemical structure that is substantially unique to erythromycin and its derivatives. The molecular weight of erythromycin A is 733.92. The empirical formula for erythromycin A is C.sub.37 H.sub.67 NO.sub.13 having a 60.55% carbon content, a 9.20% hydrogen content, a 1.91% nitrogen content, and a 28.34% oxygen content.
Clindamycin has a chemical structure indicated by its chemical name which is methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]ami no]-1-thio-L-threo-alpha-D-galacto-octopyranoside. The molecular weight of clindamycin is 424.98. The empirical formula for clindamycin is C.sub.18 H.sub.337 ClN.sub.2 O.sub.5 S having a 50.87% carbon content, a 7.83% hydrogen content, a 8.34% chlorine content, a 6.59% nitrogen content, a 18.82% oxygen content, and a 7.54% sulfur content.
Other topical treatments for acne using antibiotics are described in the following Great Britain patents: neomycin, G. B. Pat. No. 1,054,124; erythromycin, G. B. Pat. No. 1,587,428; and erythromycin derivatives in conjunction with benzoyl peroxide, G. B. Pat. Nos. 2,088,717 and 2,090,135.
Still another topical treatment for acne, more specifically acne vulgaris, includes preparation of a hyaluronic acid derivative which is a bridged conjugate of hyaluronic acid (which is a linear polymer of N-acetyl glucosamine and glucuronic acid units) bonded to a bridging agent (which is cyanogen bromide) which, in turn, is bonded to the amino-nitrogen atom of the aminopenicillin, ampicillin. Thus, with this hyaluronic acid derivative, the amino-nitrogen of the aminopenicillin is no longer in the form of a primary amino group. This hyaluronic acid derivative is disclosed in Great Britain Published Application 2,207,142.
Still other topical treatments for acne using anti-bacterials are described in the following U.S. patents: an azole derivative in conjunction with benzoyl peroxide, U.S. Pat. No. 4,446,145, incorporated herein by reference; and metronidazole in a special gel as described in U.S. Pat. No. 4,837,378, incorporated herein by reference.
It is noted that none of the topical treatments mentioned above disclose the treatment of acne topically with a cephalosporin.
It is recalled that the applicants parent U.S. patent application was filed Mar. 5, 1991. In addition, prior art treatments and proposed treatments for acne have spanned many years and have been published in a large number of publications, some of which are discussed above and some of which are discussed below.
In Kirk-Othmer, Encyclopedia of Chemical Technology, Third Edition, Volume 2, (1978), page 812, there is Table 2 in which it is disclosed that cephalosporin C, N, P were discovered in 1948; cephalothin was discovered in 1962; and cephalexin was discovered in 1967.
In Frank, "Treatment of Acne with Topical Antibiotics", Postgrad. Med., 61(6):92-8, June 1977, there is a disclosure that a number of antibiotics are used in the topical treatment of acne vulgaris. A 2% erythromycin base was used in an alcohol-water vehicle. A 0.5% tetracycline was used in an alcohol-water vehicle which also contained a penetration-enhancing material, n-decyl methyl sulfoxide [C.sub.10 SO]. Clindamycin phosphate was incorporated in an alcohol-water vehicle. Also, 1% clindamycin phosphate was incorporated in a methyl pyrrolidone vehicle.
Also, on page 98, under the subtopic "Penetrant effect of the vehicle" there is a statement that equal parts of alcohol and water (as well as C.sub.10 MSO and methyl pyrrolidone) have a penetrant effect to penetrate the canal of the sebaceous follicle. There is no mention of any form of a cephalosporin whatsoever. Thus, for fourteen years prior to the Applicants filing of the parent application, the prior art disclosed the use of the topical application of a wide variety of antibiotics to treat acne using a water/water-miscible alcohol based carrier that enhances penetration of the antibiotic into the canal of the sebaceous follicle.
Heymes (U.S. Pat. No. 4,097,595 patented in 1978) discloses novel 7-amino-thiazolyl-acetamido-cephalosporanic acid compounds of the formula (see patent for chemical structure) wherein R is selected from the group consisting of hydrogen and a group easily removable by acid hydrolysis or hydrogenolysis, R(1)is selected from the group consisting of alkyl of 1 to 4 carbon atoms, a 5 member heterocyclic ring and a 5 member heterocyclic ring containing a ketone group and A is selected from the group consisting of hydrogen, alkali metal and equivalents of alkaline earth metals, magnesium and organic amine having antibiotic activity against gram negative and gram positive bacteria and their preparation and novel intermediates thereof. These cephalosporin derivatives can be applied topically to skin for a number of conditions disclosed at column 4, lines 27-55. There is no disclosure of the treatment of acne or other acneiform disorders. The in vivo examples are only for mice infected by intraperitoneal injection of material containing microorganisms and subcutaneous administration of the cephalosporin.
In Stoughton et al, "Topical Antibiotic Therapy of Acne", Cutis, 1980, February, 25(2):216-218,220, there is a disclosure that a number of vehicles can be used to improve the skin penetrating power of topically applied antibiotics in the treatment of acne. The antibiotics were applied with their respective vehicles whose penetration was being studied, to hairless mouse skin in vitro. The antibiotics that are disclosed as being topically applied to the hairless mouse skin in vitro are erythromycin, cephalexin (a cephalosporin), troleandomycin, and minocycline. It is noted that on page 220, lines 4-6, there is a disclosure that no significant activity was shown by cephalexin in the in vitro skin penetration study.
It is noted in the last footnote on page 218 that Vehicle 3 in the study was "Vehicle/N.TM." of Neutrogena Dermatologics. Vehicle 3 includes ethyl alcohol 47.5%, purified water, laureth-4, isopropyl alcohol 4%, and propylene glycol.
In Eady et al, "The Use of Antibiotics in Acne Therapy: Oral or Topical Administration?", J Antimicrob Chemother, 1982, Aug.; 10(2):89-115, there is a disclosure that tetracycline, erythromycin, chloramphenicol, co-trimoxazole, and clindamycin are used topically in the treatment of acne. On page 104, in the second paragraph under "Conclusions", there is a background statement that "Penicillins and cephalosporins currently account for 50-65% of total antibiotic usage . . . ". However, there is no teaching that either penicillins or cephalosporins are used in the treatment of acne.
In Witkowski J. A. and Parish, L. C., "Bacterial skin infections: management of common streptococcal and staphylococcal lesions", Postgrad Med, October 1982, 72 (4), pages 166-8, 171-3, 176-8, and 181-5 in the English language, there is a disclosure that penicillin G, penicillin V, ampicillin, cefaclor (a cephalosporin), cephalexin (a cephalosporin), cefazolin (a cephalosporin), cephradine (a cephalosporin), cloxacillin, dicloxacillin, methicillin, nafcillin, and oxacillin have been used systemically to treat streptococcal and staphylococcal infection (see pages 176-177). Use of topical bacitracin, erythromycin, or neomycin is disclosed on page 182. Systemic use of penicillin is also mentioned on page 182. There is no mention of the use of topical penicillin G, penicillin V, ampicillin, cefaclor (a cephalosporin), cephalexin (a cephalosporin), cefazolin (a cephalosporin), cephradine (a cephalosporin), cloxacillin, dicloxacillin, methicillin, nafcillin, or oxacillin to topically treat streptococcal and staphylococcal infection. Furthermore, there does not appear to be any mention of the treatment of acne, either systemically or topically.
In "Cephalosporin for acne vulgaris" [letter], Sheeler R. D., J Am Acad Dermatol, June 1986, 14 (6), page 1091, there is a disclosure that the cephalosporins, cefodroxil and cefaclor, given orally were effective in reducing lesions of acne vulgaris as a side effect for treating other infections. The oral cephalosporin treatment followed an unsuccessful treatment regimen of using systemic tetracycline and topical benzoyl peroxide. There is no disclosure of the use of the cephalosporins topically to treat acne.
In AHFS Drug Information, 1990, Gerald K. McEvoy, editor, published by American Society of Hospital Pharmacists, entry on "Cephalosporins", pages 82-87, there is a discussion of cephalosporins and treatments employing cephalosporins. However, there is no disclosure of the use of cephalosporins topically. Still further, there is no topical preparation of cephalosporins disclosed. In this respect, there is no disclosure of the use of cephalosporins to treat acne topically.
In U.S. Pat. No. 4,444,755 of Horrobin, issued on Apr. 24, 1984, there is a disclosure that a number of skin disorders can be treated with gamma-linolenic acid or dibromo-gamma-linolenic acid. There is a teaching and claims to the effect that gamma-linolenic acid or dibromo-gamma-linolenic acid serve to increase prostaglandin(1) activity over prostaglandin(2) activity for the treatment a large number of skin conditions which include acne. Use of a beta-lactam antibiotic (e. g. a cephalosporin) is disclosed, and Horrobin (U.S. Pat. No. 4,444,755) teaches that the purpose of using the beta-lactam antibiotic is to enhance utilization of ester reserves of dibromo-gamma-linolenic acid (column 5, lines 63-64). The antibiotic is present in a small amount to enhance the activity of the gamma-linolenic acid which is present in a large amount. The enhancement of prostaglandin(1) series compounds is also the purpose of zinc, and this would be the purpose of "other materials influencing the 1-series/2-series PG balance in the body in favour of 1-series PG's" (column 2, lines 17-19). There is no disclosure of administering a beta-lactam antibiotic (e. g. a cephalosporin) without concomitant administration of a gamma-linolenic acid or dibromo-gamma-linolenic acid. Thus, for approximately seven years before the Applicants invention, the prior art has disclosed the use of a small, optional amount of a cephalosporin to enhance the activity of a large, required amount of administered gamma-linolenic acid or dibromo-gamma-linolenic acid in the treatment of acne.
Research relating to acne has been an active area of investigation for many years. In this respect, many publications in the medical literature have been made since the year 1979 to Feb. 12, 1993 (a date of a comprehensive computer search) relating to acne.
More specifically, a search of the MEDLINE database using Dialog Information Services for articles mentioning "acne" has revealed that in the time period spanning 1979 through Feb. 12, 1993), there were 2,524 articles. Therefore, for this fourteen year period, there was an average of more than 180 articles per year relating to acne treatment.
A more specific breakdown of a specific year versus the number of articles relating to acne treatment for that year is present in the Table as follows:
______________________________________ Table of Articles Number of Articles Year Mentioning Acne ______________________________________ 1979 176 1980 177 1981 181 1982 185 1983 204 1984 198 approx. num. before Horrobin: 82 approx. num. after Horrobin: 116 1985 206 1986 189 1987 182 1988 200 1989 160 1990 183 1991 155 approx. num. before Invention: 39 approx. num. after Invention: 116 1992 128 1993 0 (as of February 12, 1993) ______________________________________
It is recalled that Horrobin (U.S. Pat. No. 4,444,755) was published on Apr. 24, 1984, and the Applicants parent patent application was filed Mar. 5, 1991.
From the Table of Articles, the following additional facts are deduced. From the publication of Horrobin on Apr. 24, 1984 (the prior art that discloses the topical treatment of acne using a cephalosporin and gamma-linolenic acid or dibromo-gamma-linolenic acid) to the filing of the Applicants parent application on Mar. 5, 1991, approximately 1,275 articles relating to acne were published in approximately seven years.
Therefore, for approximately seven years before the Applicants filed their parent patent application, the prior art (Horrobin (U.S. Pat. No. 4,444,755)) disclosed the use of a primary active ingredient (gamma-linolenic acid or dibromo-gamma-linolenic acid) optionally with or without a cephalosporin for the topical treatment of acne. Yet, in spite of the other prior art, such as the Frank reference where an antibiotic (other than a cephalosporin) is the sole active ingredient for topical treatment of acne using a water/water-miscible alcohol carrier, only the Applicants provide a method of treating acne topically with simply a composition consisting essentially of a cephalosporin in a carrier which includes water and a water-miscible alcohol.
Moreover, the Horrobin patent does not mention use of conventional topical anti-acne ingredients selected from the group consisting of benzoyl peroxide, sulfur, resorcinol, salicylic acid, and tretinoin for topical treatment of acne. In this respect, only the Applicants invention provides for the topical use of a cephalosporin along with conventional anti-acne ingredients selected from the group consisting of benzoyl peroxide, sulfur, resorcinol, salicylic acid, and tretinoin.